M. Bozzali

White matter damage in Alzheimer's disease assessed in vivo using diffusion tensor magnetic resonance imaging

Objective: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimers disease using diffusion tensor magnetic resonance imaging (DT-MRI). Background: Although Alzheimers disease pathology mainly affects cortical grey matter, previous pathological and MRI studies showed that also the brain white matter of patients is damaged. However, the nature of Alzheimers disease associated white matter damage is still unclear. Methods: Conventional and DT-MRI scans were obtained from16 patients with Alzheimers disease and 10 sex and age matched healthy volunteers. The mean diffusivity (D̅), fractional anisotropy (FA), and inter-voxel coherence (C) of several white matter regions were measured. Results: D̅ was higher and FA lower in the corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimers disease than in the corresponding regions from healthy controls. D̅ and FA of the white matter of the occipital lobe and internal capsule were not different between patients and controls. C values were also not different between patients and controls for any of the regions studied. Strong correlations were found between the mini mental state examination score and the average overall white matter D̅ (r=0.92, p<0.001) and FA (r=0.78; p<0.001). Conclusions: White matter changes in patients with Alzheimers disease are likely to be secondary to wallerian degeneration of fibre tracts due to neuronal loss in cortical associative areas.

Magnetisation transfer ratio and mean diffusivity of normal appearing white and grey matter from patients with multiple sclerosis

OBJECTIVE To assess the feasibility of a new technique based on diffusion anisotropy to segment white and grey matter of the brain. To use this technique to measure the mean diffusivity (D̄) and magnetisation transfer ratio (MTR) of normal appearing white matter (NAWM) and grey matter (NAGM) from patients with multiple sclerosis. METHODS Dual echo turbo spin echo, MT, and diffusion weighted scans of the brain were obtained from 30 patients with multiple sclerosis and 18 sex and age matched healthy controls. After image coregistration and removal of T2 visible lesions, white and grey matter were segmented from 10 supratentorial slices using diffusion anisotropy thresholds. Histograms of the average MTR and D̄ were created for normal white and grey matter of controls and NAWM and NAGM of patients with multiple sclerosis. RESULTS All the MTR histogram derived metrics of the NAWM from patients with multiple sclerosis were significantly lower than those of white matter from controls. The peak height of the D̄histogram of NAWM from patients with multiple sclerosis was also significantly different from that of normal white matter. The average MTR, the peak location of the MTR histogram, and peak height of theD̄ histogram of the NAGM of patients with multiple sclerosis were significantly lower than the corresponding quantities of grey matter from controls. CONCLUSIONS A technique was developed for segmenting white and grey matter with the potential for improving the understanding of the pathophysiology of many neurological conditions. Its application to the study of multiple sclerosis confirms the presence of a diffuse tissue damage in the NAWM of these patients and suggests that subtle changes also occur in the NAGM.

Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis

OBJECTIVES To assess (a) whether the changes in the normal appearing brain tissue (NABT), as revealed by magnetisation transfer (MT) histogram analysis, correlates with cognitive dysfunction in patients with multiple sclerosis and (b) the relative contribution of these changes by comparison with that of multiple sclerosis lesions visible on conventional MRI. METHODS Dual echo, T1 weighted and MT scans of the brain were obtained in 12 patients with multiple sclerosis with cognitive impairment and in seven without cognitive impairment. Lesion loads were assessed from T2 and T1 weighted scans. To create MT histograms of the NABT, multiple sclerosis lesion outlines from dual echo scans were superimposed automatically and nulled out from the coregistered and scalp stripped MTR maps. Average lesion MT ratio (MTR) and brain size were also measured. RESULTS T2 and T1 lesion loads were significantly higher and the average lesion MTR and brain size were significantly lower in the group of cognitively impaired patients. Patients with cognitive deficits also had significantly lower average MTR and peak location of the NABT histogram. Logistic regression analysis showed that 68% of the total variance was explained by average NABT-MTR alone. A multivariable regression model showed that NABT-MTR was the only factor that significantly correlated with cognitive impairment in these patients (p=0.001). CONCLUSIONS The extent of abnormalities which go undetected when using conventional MRI is relevant in determining cognitive impairment in multiple sclerosis.

A magnetization transfer histogram study of normal-appearing brain tissue in MS

Objective: To evaluate 1) the ability of magnetization transfer ratio (MTR) histogram analysis to detect the extent of changes occurring outside MS lesions seen on conventional scans, 2) whether such changes vary in the different MS clinical phenotypes, 3) whether the changes are associated with the extent and severity of the macroscopic lesion load, and 4) the contribution to brain atrophy. Methods: Dual-echo, T1-weighted, and MT scans of the brain were obtained from 77 patients with varying MS courses and 20 age- and sex-matched control subjects. To create MT histograms of the normal-appearing cerebral tissue, MS lesions were segmented from dual-echo scans, superimposed automatically, and nulled out from the coregistered and scalp-stripped MTR maps. Average MTR, peak height, and peak position were considered. T2 and T1 lesion loads, average lesion MTR, and brain volume were also measured. Results: Average histogram MTR (p < 0.0001) and peak position (p < 0.0001) from patients with relapsing–remitting MS (RMMS) were lower than those from control subjects. Patients with primary progressive MS (PPMS) had lower average histogram MTR (p = 0.002) and histogram peak height (p = 0.01) than control subjects. Patients with secondary progressive MS (SPMS) had a lower peak height (p = 0.05) than those with RRMS. Average lesion MTR (p < 0.0001) correlated highly with the histogram MTR. Average histogram MTR (p < 0.0001) and T2 lesion load (p = 0.001) correlated highly with brain volume. Conclusions: The amount of microscopic changes account for an important fraction of the lesion load in MS. They may contribute to the development of brain atrophy and tend to be more evident in patients with secondary progressive MS.

Quantification of tissue damage in AD using diffusion tensor and magnetization transfer MRI

The authors measured mean diffusivity (D̄) and magnetization transfer ratio (MTR) of the brain from 18 patients with AD and 16 healthy control subjects. The peak heights of cortical gray matter (cGM) D̄ (p < 0.001) and MTR (p < 0.001) histograms were lower and average cGM D̄ (p < 0.01) higher in patients with AD than in control subjects. A composite MR score based on brain volume and cGM MTR peak height was correlated with patient cognitive impairment (r = 0.65, p = 0.003). This preliminary study presents a novel approach to quantify AD-related tissue damage in-vivo.

A conventional and magnetization transfer MRI study of the cervical cord in patients with MS

Objective: To evaluate the contribution made by cervical cord damage, assessed using a fast short-tau inversion recovery (fast-STIR) sequence and magnetization transfer ratio (MTR) histogram analysis to the clinical manifestations of MS. Background: Previous studies have failed to show significant correlations between the number and extent of T2 spinal cord lesions and the clinical status of patients with MS. Fast-STIR is more sensitive than T2-weighted imaging for detecting cervical cord MS lesions. MTR histogram analysis provides estimates of the overall disease burden in the cervical cord with higher pathologic specificity to the more destructive aspects of MS than T2-weighted scans. Methods: We obtained fast-STIR and magnetization transfer (MT) scans from 96 patients with MS (52 with relapsing-remitting [RRMS], 33 with secondary progressive [SPMS], and 11 with primary progressive [PPMS] MS) and 21 control subjects. Dual-echo scans of the brain were also obtained and lesion load measured. Results: Eighty-one of the patients with MS had an abnormal cervical cord scan. Patients with SPMS had more cervical cord lesions and more images with visible cervical cord damage than did patients with RRMS or PPMS (p = 0.04). The entire cohort of patients with MS had lower average MTR of the cervical cord (p = 0.006) than control subjects. Compared to control subjects, patients with RRMS had similar cervical cord MTR histogram-derived measures, whereas those with PPMS had lower average MTR (p = 0.01) and peak height (p = 0.02). Patients with SPMS had lower histogram peak height than did those with RRMS (p = 0.03). The peak position and height of the cervical cord MTR histogram were independent predictors of the probability of having locomotor disability. We found no correlation between brain T2 lesion load and any of the cervical cord MTR histogram metrics. Conclusions: This study shows that the amount and severity of MS pathology in the cervical cord are greater in the progressive forms of the disease. An accurate assessment of cervical cord damage in MS gives information that can be used in part to explain the clinical manifestations of the disease.

A whole brain MR spectroscopy study from patients with Alzheimer's disease and mild cognitive impairment

Brain damage in Alzheimers disease (AD) and mild cognitive impairment (MCI) is widespread with involvement of large portions of the neocortex and the subcortical white matter. A quantitative measure of neuronal damage of the entire brain might be valuable in the context of large-scale, longitudinal studies of these patients. This study investigated the extent of neuroaxonal injury of patients with AD and MCI using a novel unlocalized proton magnetic resonance spectroscopy ((1)H-MRS) technique, which allows quantification of the concentration of N-acetylaspartate from the whole of the brain tissue (WBNAA). Conventional brain MRI and WBNAA were obtained from 28 AD patients, 27 MCI patients and 25 age-matched controls. Normalized brain volume (NBV) was also measured using an automated segmentation technique. WBNAA and NBV showed a significant heterogeneity between groups (P < 0.001). WBNAA concentration was different between controls and MCI patients (P = 0.003), but not between MCI and AD patients (P = 0.33). NBV differed both between controls and MCI patients (P = 0.02) and between MCI and AD patients (P = 0.03). A multivariate regression model retained WBNAA as the best MRI predictor of the Mini Mental State Examination score (P = 0.001). Significant neuronal damage, which is related to the extent of cognitive decline, can be quantified in the whole brain tissue of patients with AD, using a novel (1)H-MRS approach. The demonstration in patients with MCI of MR structural and metabolic findings, intermediate between those of healthy volunteers and those of AD patients, indicates that neuronal damage is already evident and widespread in individuals with MCI before they are clinically demented.

Intra-voxel and inter-voxel coherence in patients with multiple sclerosis assessed using diffusion tensor MRI

Abstract. Previous diffusion tensor magnetic resonance imaging (DT-MRI) studies reported mean diffusivity (n

Magnetization transfer and diffusion tensor MR imaging of basal ganglia from patients with multiple sclerosis

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An MT MRI study of the cervical cord in clinically isolated syndromes suggestive of MS

) and fractional anisotropy (FA) changes in lesions and normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS), but neglected the additional information which can be obtained by the analysis of the inter-voxel coherence (C). The present study is based on a large sample of patients with MS and it is aimed at assessing the potential role of C in the quantification of MS-related tissue damage of T2-visible lesions and NAWM. We obtained dual-echo, T1-weighted and DT-MRI scans from 78 patients with relapsing-remitting (RR), secondary progressive (SP), or primary progressive (PP) MS and from 26 healthy volunteers. We calculated n